Affinage

PYCR1

Pyrroline-5-carboxylate reductase 1, mitochondrial · UniProt P32322

Length
319 aa
Mass
33.4 kDa
Annotated
2026-06-10
86 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PYCR1 is a mitochondrial enzyme that catalyzes the final NAD(P)H-dependent reduction of Δ1-pyrroline-5-carboxylate (P5C) to L-proline, coupling de novo proline biosynthesis to cellular redox balance and oxidative-stress resistance (PMID:33734376, PMID:33109600). Crystallographic and kinetic work defines an active site with adjacent P5C-substrate and NAD(P)H-binding pockets that accommodate competitive and dual-site inhibitors and undergoes conformational change on ligand binding (PMID:33109600, PMID:38411104, PMID:41016381), and the enzyme also reduces Δ1-piperideine-6-carboxylate to L-pipecolic acid, giving it a role in lysine degradation (PMID:24431009). Its catalytic output is redox-directed: by oxidizing NADH to NAD+ during proline synthesis, PYCR1 lowers the NADH/NAD+ ratio and sustains TCA-cycle flux under IDH1-mutant and hypoxic conditions, with loss of PYCR1 driving hypoxia and cell death in tumors (PMID:29562167, PMID:35108535). Enzyme activity is tuned post-translationally through SIRT3-mediated deacetylation at K228, which favors active-decamer formation and opposes CBP acetylation (PMID:31108370, PMID:35716330), while protein stability is controlled by phosphorylation-coupled ubiquitination involving ITPKA/Stub1 (PMID:39170313) and BHLHE41 (PMID:38811952). Beyond catalysis, hypoxic IGF1R-driven phosphorylation at Y135 recruits nuclear PYCR1 to ELK4 target promoters where its NAD+ production fuels Sirt7-dependent H3K18ac removal, linking the enzyme to transcriptional control (PMID:37777542). PYCR1 supports oxidative-stress defense via direct interaction with DJ-1 (PARK7) and assembly with RRM2B/PYCR2 (PMID:23743200, PMID:26733354), and in cancer-associated fibroblasts its proline output drives collagen production and extracellular-matrix remodeling that promote tumor growth and metastasis (PMID:35760868). Loss-of-function PYCR1 mutations cause a connective-tissue/progeroid phenotype with mitochondrial dysfunction, increased apoptosis under oxidative stress, and reduced enzymatic activity from misfolding-prone alleles (PMID:19648921, PMID:39172257).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2009 High

    Established that PYCR1 is a mitochondrial protein whose loss compromises mitochondrial integrity and survival, framing it as a redox/stress-resistance factor rather than a purely metabolic enzyme.

    Evidence Subcellular fractionation, patient fibroblast membrane-potential and apoptosis assays, and morpholino knockdown in Xenopus and zebrafish

    PMID:19648921

    Open questions at the time
    • Did not define the catalytic mechanism linking PYCR1 to membrane potential
    • Did not identify protein partners mediating stress resistance
  2. 2013 High

    Identified a direct partner (DJ-1/PARK7) that enhances PYCR1 activity, placing PYCR1 on a defined anti-oxidative-stress pathway.

    Evidence Reciprocal Co-IP, in vitro binding, in vitro activity assay, co-localization, and double-knockdown epistasis

    PMID:23743200

    Open questions at the time
    • Structural basis of DJ-1 binding not resolved
    • Whether DJ-1 alters oligomeric state untested
  3. 2014 High

    Demonstrated PYCR1 has a second substrate, reducing P6C to pipecolic acid, extending its role to lysine degradation.

    Evidence In vitro kinetic assay with commercial PYCR1 plus LC-MS/MS, validated with antiquitin-deficient patient urine

    PMID:24431009

    Open questions at the time
    • Physiological significance of pipecolic acid synthesis in vivo unquantified
  4. 2016 Medium

    Placed PYCR1 in a higher-order complex with RRM2B and PYCR2 required for RRM2B-mediated oxidative protection.

    Evidence Flag-RRM2B complex purification with MS plus shRNA silencing under oxidative stress

    PMID:26733354

    Open questions at the time
    • Stoichiometry and direct vs. indirect contacts within the complex unknown
    • Single-lab finding without reciprocal pulldown
  5. 2018 High

    Connected PYCR1 catalysis to redox homeostasis by showing it oxidizes NADH to NAD+ to lower the NADH/NAD+ ratio in IDH1-mutant cells, partially uncoupling the ETC from the TCA cycle.

    Evidence Glutamine-to-proline isotope tracing, NADH/NAD+ measurement, oxygen consumption, and activity assays

    PMID:29562167

    Open questions at the time
    • Generality beyond IDH1-mutant context not addressed here
  6. 2019 High

    Defined post-translational control of PYCR1 activity through SIRT3 deacetylation and CBP acetylation at K228 governing decamer assembly.

    Evidence IP-MS, in vitro binding, K228 mutagenesis, activity assays, and native PAGE oligomer analysis

    PMID:31108370

    Open questions at the time
    • Stimuli that trigger SIRT3/CBP switching on PYCR1 not defined
    • Whether other lysines are modified untested
  7. 2019 Medium

    Linked PYCR1 to signaling control by showing it interacts with STAT3 and acts upstream of STAT3-mediated proliferation and EMT programs.

    Evidence Co-IP and siRNA knockdown with STAT3 overexpression rescue in colorectal cancer cells

    PMID:31606203

    Open questions at the time
    • Direct vs. indirect PYCR1-STAT3 binding not resolved by reciprocal validation
    • Mechanism connecting enzyme activity to STAT3 unclear
  8. 2020 High

    Showed PYCR1 activity rises under hypoxia and sustains TCA-cycle flux, making it required for tumor cell survival in low-oxygen microenvironments.

    Evidence Loss-of-function with metabolic flux, 3D spheroid, and in vivo hypoxia imaging

    PMID:35108535

    Open questions at the time
    • How hypoxia increases PYCR1 activity mechanistically not fully defined
  9. 2020 Medium

    Implicated a Lon chaperone-PYCR1 client relationship and downstream ROS/EMT signaling in cancer cells.

    Evidence Lon-PYCR1 interaction, ROS measurement, EMT markers, and signaling Western blots

    PMID:31987921

    Open questions at the time
    • Whether Lon regulates PYCR1 folding or stability directly untested
    • Single-lab functional readouts
  10. 2021 High

    Confirmed PYCR1 and PYCR2 are functionally redundant P5C reductases by yeast complementation and double-mutant mouse lethality.

    Evidence Fibroblast localization, yeast Pro3 complementation, and single/double-null mouse genetics

    PMID:33734376

    Open questions at the time
    • Tissue-specific division of labor between PYCR1 and PYCR2 not delineated
  11. 2021 Medium

    Identified m6A-dependent transcript regulation of PYCR1 via a USP18-FTO axis controlling its protein levels in bladder cancer.

    Evidence m6A modification, mRNA stability, FTO activity, and protein-level Western blots

    PMID:33461172

    Open questions at the time
    • Direct FTO occupancy on PYCR1 mRNA sites not mapped
    • Single-lab finding
  12. 2022 High

    Established PYCR1 as the key proline-synthesizing enzyme in cancer-associated fibroblasts driving collagen and ECM-dependent tumor growth and metastasis.

    Evidence Glutamine-to-proline isotope tracing in CAFs, PYCR1 knockdown, xenografts, and collagen quantification

    PMID:35760868

    Open questions at the time
    • Mechanism by which acetyl-CoA epigenetically upregulates proline synthesis not fully detailed
  13. 2022 Medium

    Consolidated transcriptional and epigenetic control of PYCR1 through STAT3/SENP3, promoter hypomethylation, and p300-H3K27ac, plus a SIRT3-dependent CRIF1 input on activity.

    Evidence Promoter binding/ChIP, methylation analysis, and SIRT3 deacetylation rescue across bladder, gastric, and NSCLC models

    PMID:35654390 PMID:35716330 PMID:36227136

    Open questions at the time
    • Relative contribution of each regulatory layer in a given tissue unresolved
    • Mostly single-lab per-axis findings
  14. 2022 Medium

    Linked PYCR1 to ferroptosis resistance via SLC25A10, suppressing lipid ROS in colorectal cancer.

    Evidence Overexpression/silencing, lipid ROS measurement, ferroptosis pharmacology, and SLC25A10 rescue

    PMID:36104652

    Open questions at the time
    • Direct mechanism connecting PYCR1 to SLC25A10 expression unknown
    • Single-lab epistasis
  15. 2023 High

    Revealed a moonlighting transcriptional role: hypoxic IGF1R phosphorylation at Y135 drives nuclear PYCR1 to ELK4 promoters where NAD+ production fuels Sirt7-dependent H3K18ac deacetylation.

    Evidence Phosphosite identification, Co-IP, ChIP, NAD+ and Sirt7 activity assays, and Y135 phosphomutant functional assays

    PMID:37777542

    Open questions at the time
    • Breadth of ELK4 target genes regulated this way not mapped
    • Balance between nuclear and mitochondrial PYCR1 pools undefined
  16. 2024 Medium

    Defined protein-stability control of PYCR1 by opposing ubiquitin pathways: ITPKA-S29 phosphorylation blocks Stub1 ubiquitination while BHLHE41 promotes its degradation.

    Evidence Co-IP, phosphosite identification, ubiquitination and protein-stability assays in glioma and bladder cancer

    PMID:38811952 PMID:39170313

    Open questions at the time
    • Whether these inputs converge on the same lysines unknown
    • Single-lab per-axis evidence
  17. 2024 Medium

    Positioned PYCR1 as a scaffold/regulator of EGFR stability and TLR/NF-κB signaling through a USP11-EGFR deubiquitination complex and interactions with TRAF6/TAK1/ECSIT/TAB2.

    Evidence CRISPR KO, Co-IP, MS, EGFR ubiquitination, and NF-κB activation assays; replicated EGFR interaction across cancers

    PMID:37293856 PMID:40102683 PMID:41254241

    Open questions at the time
    • Whether EGFR/signaling roles depend on catalytic activity untested
    • Direct vs. complex-mediated contacts not all reciprocally validated
  18. 2024 Medium

    Showed PYCR1 supports immune and apoptotic phenotypes — promoting Th2 differentiation via a mitochondrial TREMP micropeptide and conferring TRAIL resistance by sequestering death receptors from the surface.

    Evidence Co-IP, PYCR1-KO mice with airway allergy model; flow cytometry of surface death receptors and caspase assays

    PMID:38549801 PMID:39025723

    Open questions at the time
    • Molecular basis of death-receptor redistribution unknown
    • Whether TREMP alters PYCR1 catalysis untested
  19. 2024 High

    Provided structural and chemical-biology tools defining the PYCR1 active site, including a co-crystal with a competitive inhibitor and dual-site fragment binders.

    Evidence X-ray crystallography (inhibitor co-crystals and fragment screens), kinetic inhibition, MD simulations, and cell-based proline assays

    PMID:33109600 PMID:38411104 PMID:41016381

    Open questions at the time
    • No structure of the active decamer with cofactor in catalytic cycle reported here
    • Cryptic subpocket druggability in cells unconfirmed
  20. 2024 Medium

    Tied PYCR1 disease alleles to enzymatic loss-of-function, showing a missense mutation reduces activity via misfolding.

    Evidence In vitro activity assay of mutant vs. wild-type plus 3D structural modeling

    PMID:39172257

    Open questions at the time
    • Single mutation, single patient
    • Cellular consequences of misfolding not assessed
  21. 2025 Medium

    Connected PYCR1 to organelle-quality-control and metabolic-gene programs, activating PINK1/Parkin mitophagy for stemness and influencing H3K18-lactylation/autophagy-linked immune evasion.

    Evidence ChIP (H3K4me3, H3K18la), metabolomics/transcriptomics, mitophagy markers, CD8+ T-cell cytotoxicity, and in vivo models

    PMID:39422696 PMID:40341538 PMID:40848149

    Open questions at the time
    • Causal chain from proline/NAD+ output to lactylation and mitophagy not fully resolved
    • Single-lab per-pathway findings

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single mitochondrial reductase is partitioned between its catalytic, redox-buffering, nuclear-transcriptional, and signaling-scaffold roles — and which roles depend on enzymatic activity versus protein scaffolding — remains unresolved.
  • No unified model integrating mitochondrial, nuclear, and scaffold functions
  • Activity-dependence of EGFR/TLR/STAT3 roles untested
  • Structure of catalytically active decamer with bound cofactor not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0016787 hydrolase activity 2
Localization
GO:0005739 mitochondrion 4 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-8953897 Cellular responses to stimuli 3
Partners
BHLHE41EGFRITPKAPARK7PYCR2RRM2BSTAT3USP11
Complex memberships
PYCR1-EGFR-USP11 deubiquitination complexPYCR1-PYCR2-RRM2B complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 PYCR1 protein localizes to mitochondria; loss-of-function mutations cause altered mitochondrial morphology, reduced membrane potential, and increased apoptosis under oxidative stress in patient fibroblasts; knockdown of orthologs in Xenopus and zebrafish causes epidermal hypoplasia with massive apoptosis. Subcellular fractionation/localization, patient fibroblast functional assays, morpholino knockdown in Xenopus and zebrafish Nature genetics High 19648921
2013 DJ-1 (PARK7 gene product) directly binds PYCR1 both in vivo and in vitro; DJ-1 enhances PYCR1 enzymatic activity in vitro; both proteins co-localize in mitochondria; epistasis experiments (double knockdown showing no additivity) place them on the same anti-oxidative stress pathway. Co-immunoprecipitation, in vitro binding assay, in vitro enzymatic activity assay, fluorescence co-localization, genetic epistasis (double knockdown) Biochemical and biophysical research communications High 23743200
2016 PYCR1 physically interacts with RRM2B (ribonucleotide reductase small subunit B) and PYCR2 as components of the same protein complex; dual silencing of PYCR1 and PYCR2 causes mitochondrial network fragmentation and hypersensitivity to oxidative stress, and abolishes the anti-oxidation activity of RRM2B overexpression. Large-scale Flag-RRM2B complex purification followed by mass spectrometry identification; shRNA silencing with oxidative stress phenotypic readout Scientific reports Medium 26733354
2018 In IDH1-R132H mutant cells, enhanced PYCR1 activity oxidizes NADH to NAD+ during proline synthesis from glutamine, thereby partially uncoupling the electron transport chain from TCA cycle activity and maintaining a lower NADH/NAD+ ratio. Stable isotope tracing (glutamine-derived proline), NADH/NAD+ ratio measurement, oxygen consumption assays, PYCR1 activity assays in IDH1-mutant vs. wild-type cells Cell reports High 29562167
2019 SIRT3 deacetylates PYCR1 at lysine K228; CBP is the acetyltransferase that acetylates PYCR1 at K228; acetylation at K228 reduces PYCR1 enzymatic activity by impairing formation of the PYCR1 decamer; SIRT3-mediated deacetylation increases PYCR1 activity and promotes cell proliferation. Immunoprecipitation and mass spectrometry to identify SIRT3-PYCR1 interaction; in vitro binding; site-directed mutagenesis (K228); enzymatic activity assays; native PAGE to assess oligomeric state Neoplasia High 31108370
2019 PYCR1 directly interacts with STAT3 (demonstrated by co-immunoprecipitation); STAT3 overexpression partially reverses the effects of PYCR1 knockdown on proliferation, drug resistance, and EMT in colorectal cancer cells, placing PYCR1 upstream of STAT3-mediated p38 MAPK and NF-κB signaling. Co-immunoprecipitation (CoIP) assay; siRNA knockdown with STAT3 overexpression rescue; Western blot for pathway proteins Biochemical and biophysical research communications Medium 31606203
2020 Mitochondrial Lon chaperone protein binds PYCR1 as a client; Lon-dependent PYCR1 activity induces mitochondrial ROS production, which drives EMT via p38 and NF-κB signaling in cancer cells. Protein-protein interaction identification (Lon-PYCR1 client relationship), ROS measurement, EMT marker assays, signaling pathway Western blots Cancer letters Medium 31987921
2020 In hypoxic conditions, mitochondrial PYCR1 activity is increased; PYCR1 oxidizes NADH coupled to proline synthesis, permitting continued TCA cycle activity; loss of PYCR1 leads to increased hypoxia in vivo and in 3D culture, resulting in widespread cell death. PYCR1 knockdown/knockout under hypoxic conditions; metabolic flux assays; 3D spheroid culture; in vivo tumor models with hypoxia imaging Cell reports High 35108535
2020 PYCR1 knockdown in lung adenocarcinoma (LUAD) significantly increases phosphorylation of JAK2 and STAT3 and elevates Bcl-2 and c-Myc expression, indicating that PYCR1 activity suppresses JAK/STAT signaling in LUAD cells. siRNA knockdown, Western blot for JAK2 and STAT3 phosphorylation, functional proliferation/migration assays Molecular carcinogenesis Low 32133692
2021 USP18 deubiquitinates FTO post-translationally, increasing FTO protein levels; elevated FTO then demethylates N6-methyladenosine (m6A) on PYCR1 mRNA, stabilizing the transcript and increasing PYCR1 protein in bladder cancer. Western blot for protein levels, m6A modification assays, mRNA stability assays, FTO enzymatic activity Aging Medium 33461172
2021 Both PYCR1 and PYCR2 localize to mitochondria in fibroblasts; both can complement loss of yeast Pro3 (the yeast P5C-to-proline enzyme), confirming their enzymatic activity as P5C reductases; Pycr1 and Pycr2 double-mutant mice are sub-viable, indicating the genes are largely functionally redundant in proline biosynthesis. Fluorescence localization in fibroblasts; yeast complementation assay; mouse genetics (single and double null alleles) Genetics High 33734376
2022 PYCR1 is the key enzyme for de novo proline synthesis from glutamine in cancer-associated fibroblasts (CAFs); reducing PYCR1 levels in CAFs decreases tumor collagen production, tumor growth, and metastatic spread; proline synthesis in CAFs is epigenetically upregulated by increased pyruvate dehydrogenase-derived acetyl-CoA levels. Stable isotope tracing (glutamine-to-proline in CAFs), PYCR1 knockdown in CAFs, in vivo xenograft models, collagen quantification Nature metabolism High 35760868
2022 PYCR1 overexpression inhibits lipid reactive oxygen species (ROS) production and promotes SLC25A10 expression in colorectal cancer cells; SLC25A10 overexpression reverses the anti-tumor effects of PYCR1 silencing, placing SLC25A10 downstream of PYCR1 in ferroptosis resistance. PYCR1 overexpression/silencing, lipid ROS measurement, ferroptosis inhibitor/inducer pharmacological experiments, SLC25A10 overexpression rescue Human cell Medium 36104652
2022 SENP3 promotes STAT3 deSUMOylation, increasing nuclear STAT3; nuclear STAT3 then directly binds the PYCR1 gene promoter to transcriptionally upregulate PYCR1 expression in bladder cancer. SENP3/STAT3 Western blot and nuclear fractionation; STAT3 promoter binding to PYCR1 (inferred from context of transcription factor function on PYCR1 promoter) Aging Medium 36227136
2022 CRIF1 promotes PYCR1 deacetylation and increased enzymatic activity via SIRT3; PYCR1 deacetylation reverses the anti-tumor effect of CRIF1 knockdown in NSCLC cells, placing CRIF1-SIRT3-PYCR1 in the same pathway. SIRT3-mediated deacetylation assay, PYCR1 enzymatic activity assays, CRIF1 knockdown with PYCR1 deacetylation rescue, flow cytometry for apoptosis Journal of molecular histology Medium 35716330
2023 Under hypoxia, nuclear IGF1R phosphorylates PYCR1 at Tyrosine 135; this phosphorylation promotes PYCR1 binding to ELK4 transcription factor and recruitment to ELK4-target gene promoters; PYCR1-catalyzed NAD+ production stimulates Sirt7 deacetylase activity on H3K18ac, mediating transcriptional repression and supporting tumor cell growth under hypoxia. Phosphorylation site identification (Y135), co-immunoprecipitation (PYCR1-ELK4), ChIP assay (PYCR1 at gene promoters), enzymatic NAD+ production assay, Sirt7 deacetylase activity assay, PYCR1 Y135 phosphomutant functional assays Nature communications High 37777542
2023 PYCR1 promotes NSCLC progression through JAK-STAT3 signaling, which is mediated via PRODH-dependent glutamine synthesis; PYCR1 activates STAT3 phosphorylation and promotes PD-L1 transcription by elevating STAT3 binding to the PD-L1 gene promoter. PYCR1 overexpression with siPRODH and STAT3 inhibitor (stattic) rescue; ChIP assay for STAT3 binding to PD-L1 promoter; luciferase assay for PD-L1 transcription Translational oncology Medium 37018868
2024 PYCR1 interacts with EGFR by co-immunoprecipitation; PYCR1 knockout inhibits proliferation, migration, and colony formation; in NSCLC, PYCR1 stabilizes EGFR by forming a complex with EGFR and USP11, enhancing EGFR deubiquitination and stability; PYCR1 also promotes TLR signaling by interacting with TRAF6, TAK1, ECSIT, and TAB2, facilitating their ubiquitination and NF-κB activation. CRISPR-Cas9 PYCR1-KO, co-immunoprecipitation, mass spectrometry, EGFR ubiquitination assay, NF-κB activation assay, pharmacological inhibition with PYCR1-IN-1 Experimental & molecular medicine Medium 41254241
2024 PYCR1 interacts with EGFR (co-immunoprecipitation); aerobic glycolysis and the EGFR/PI3K/AKT pathway are required downstream of PYCR1 in bladder cancer; EGFR inhibitor CL-387785 inhibits the EGFR/PI3K/AKT pathway and attenuates effects of PYCR1 overexpression but has no effect on PYCR1 expression itself. Co-immunoprecipitation, PYCR1 knockdown/overexpression, EGFR inhibitor treatment, glycolysis assays International journal of oncology Medium 37293856
2024 BHLHE41 directly interacts with PYCR1 (co-immunoprecipitation); BHLHE41 decreases PYCR1 protein stability by promoting its ubiquitination and proteasomal degradation, thereby inactivating the PI3K/AKT signaling pathway in bladder cancer. Co-immunoprecipitation, ubiquitination assay, protein stability assays, rescue experiments with PYCR1 overexpression European journal of medical research Medium 38811952
2024 ITPKA kinase interacts with PYCR1 and phosphorylates PYCR1 at serine 29; this phosphorylation inhibits E3 ligase Stub1-mediated ubiquitination of PYCR1, thereby stabilizing PYCR1 protein and contributing to glioma progression. Protein-protein interaction (co-immunoprecipitation), phosphorylation site identification (S29), ubiquitination assay, protein stability assay Heliyon Medium 39170313
2024 PYCR1 knockout in liver cancer cells inhibits glycolysis and reduces H3K18 lactylation of the IRS1 histone, thereby inhibiting IRS1 expression; this pathway links PYCR1 activity to metabolic gene regulation via histone lactylation. PYCR1 knockout, metabolomics, transcriptome sequencing, ChIP assay for H3K18 lactylation at IRS1 promoter Clinical and translational medicine Medium 39422696
2024 PYCR1 interacts with EGFR and promotes esophageal squamous cell carcinoma progression and metastasis by activating the PI3K/AKT/mTOR signaling pathway; EGFR overexpression reverses the inhibitory effects of PYCR1 knockdown. Co-immunoprecipitation, mass spectrometry, immunofluorescence, proteomic analysis, EGFR overexpression rescue, in vivo xenograft The journal of gene medicine Medium 40102683
2024 The micropeptide TREMP (encoded by lincR-PPP2R5C) localizes to mitochondria and interacts with PYCR1; this interaction enhances glycolysis and promotes Th2 cell differentiation; PYCR1 knockout mice show attenuated allergic airway inflammation similar to TREMP knockout mice. Co-immunoprecipitation (TREMP-PYCR1), CRISPR PYCR1-KO mice, glycolysis measurement, Th2 differentiation assays, in vivo HDM allergy model Allergology international Medium 39025723
2024 Homozygous missense mutation p.Ala187Thr in PYCR1 decreases enzymatic activity in vitro; 3D structural modeling shows the mutation alters hydrogen bonds causing protein misfolding. In vitro enzymatic activity assay of mutant vs. wild-type PYCR1, 3D structural modeling Molecular genetics and genomics Medium 39172257
2014 PYCR1 can reduce Δ1-piperideine-6-carboxylate (P6C) to L-pipecolic acid with a Km of similar magnitude to its Km for P5C-to-proline conversion; this was confirmed using urine from antiquitin-deficient patients accumulating P6C, demonstrating PYCR1 has an alternative substrate in lysine degradation. In vitro enzymatic assay with commercial PYCR1 and P6C substrate; LC-MS/MS quantification of substrate/product; confirmation with patient urine samples Journal of inherited metabolic disease High 24431009
2020 X-ray crystal structure of human PYCR1 complexed with N-formyl-L-proline (NFLP) reveals that inhibitor binding induces conformational changes in the active site including translation of an α-helix by 1 Å; NFLP competitively inhibits PYCR1 with respect to P5C substrate (Ki = 100 μM) and phenocopies PYCR1 knockdown in breast cancer cells by inhibiting de novo proline biosynthesis. X-ray crystallography (co-crystal structure), competitive inhibition kinetics, cell-based proline biosynthesis assay, spheroid growth assay The Journal of biological chemistry High 33109600
2024 Fragment-based crystallographic screening identified eight fragment hits binding to human PYCR1; novel fragments block both the P5C substrate pocket and the NAD(P)H binding site (dual-site binders); four hits show enzymatic inhibition, demonstrating the active site architecture accommodates dual-site inhibitors. X-ray crystallography fragment screening (22% hit rate), kinetic inhibition assays Journal of chemical information and modeling High 38411104
2025 Crystallographic fragment screening against PYCR1 revealed ligands occupying P5C and NADH binding pockets including dual-site ligands; sulfonamide and sulfamate groups are isosteric replacements for the carboxylate in the active site; a cryptic subpocket near the nicotinamide-binding site was identified; ligand-induced conformational changes were confirmed by molecular dynamics to be intrinsically accessible. X-ray crystallography (12 co-crystal structures), molecular dynamics simulations Bioorganic chemistry High 41016381
2025 SMYD2 methyltransferase upregulates PYCR1 expression through H3K4me3 histone modification at the PYCR1 locus; elevated PYCR1 subsequently activates the PINK1/Parkin mitophagy pathway, supporting bladder cancer stem cell stemness maintenance. H3K4me3 ChIP assay at PYCR1 promoter, siRNA knockdown of SMYD2/PYCR1, mitophagy markers (LC3B, PINK1, Parkin), cancer stem cell assays International journal of oncology Medium 40341538
2025 FOXA1 transcription factor directly activates PYCR1 transcription (ChIP assay); elevated PYCR1 activates autophagy in LUAD cells, which suppresses CD8+ T cell-mediated anti-tumor killing; PYCR1 overexpression reverses the effect of FOXA1 knockdown. ChIP assay (FOXA1 binding to PYCR1 promoter), dual-luciferase assay, PYCR1 knockdown/overexpression, CD8+ T cell cytotoxicity assay, in vivo mouse experiments Cancer immunology, immunotherapy Medium 40848149
2022 Hypomethylation at a CpG island in the PYCR1 promoter and p300-induced H3K27ac modification at the PYCR1 promoter both contribute to PYCR1 transcriptional upregulation in gastric cancer. DNA methylation analysis (bisulfite sequencing/bioinformatics), ChIP for H3K27ac, p300 acetyltransferase functional experiments Biochimica et biophysica acta. Gene regulatory mechanisms Medium 35654390
2019 Pycr1 knockout zebrafish show markedly reduced proline and extracellular matrix contents, lowered energy, diminished superoxide dismutase and telomerase activity, increased apoptosis and senescence from embryo stage, and a progeria-like phenotype; adult pycr1 KO fish display reduced locomotion, aggression, social interaction, and dysregulated circadian rhythm. CRISPR/Cas9 pycr1 knockout zebrafish, biochemical assays (proline, ECM, ATP, SOD, telomerase), apoptosis/senescence staining, behavioral testing Cells High 31091804
2024 PYCR1 regulates TRAIL resistance in NSCLC by preventing redistribution of death receptors (DRs) to the plasma membrane; PYCR1 knockdown increases DR surface localization, activates Caspase-3/8, and sensitizes cells to TRAIL-induced apoptosis; PYCR1 overexpression reduces DR surface distribution and suppresses Caspase-3/8 activation. PYCR1 knockdown/overexpression, flow cytometry for surface DR localization, Caspase-3/8 activity assays, TRAIL sensitivity assays Oncology letters Medium 38549801

Source papers

Stage 0 corpus · 86 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mutations in PYCR1 cause cutis laxa with progeroid features. Nature genetics 178 19648921
2022 Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. Nature metabolism 134 35760868
2020 Mitochondrial oxidative stress by Lon-PYCR1 maintains an immunosuppressive tumor microenvironment that promotes cancer progression and metastasis. Cancer letters 119 31987921
2017 Knockdown of PYCR1 inhibits cell proliferation and colony formation via cell cycle arrest and apoptosis in prostate cancer. Medical oncology (Northwood, London, England) 78 28078560
2018 Oncogenic IDH1 Mutations Promote Enhanced Proline Synthesis through PYCR1 to Support the Maintenance of Mitochondrial Redox Homeostasis. Cell reports 72 29562167
2016 PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress. Scientific reports 66 26733354
2022 Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions. Cell reports 60 35108535
2019 Knockdown of PYCR1 inhibits proliferation, drug resistance and EMT in colorectal cancer cells by regulating STAT3-Mediated p38 MAPK and NF-κB signalling pathway. Biochemical and biophysical research communications 57 31606203
2018 PYCR1 promotes the progression of non-small-cell lung cancer under the negative regulation of miR-488. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 54 30605882
2024 PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification. Clinical and translational medicine 51 39422696
2021 Dysregulation of USP18/FTO/PYCR1 signaling network promotes bladder cancer development and progression. Aging 51 33461172
2013 Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. Molecular genetics and metabolism 51 24035636
2020 PYCR1 knockdown inhibits the proliferation, migration, and invasion by affecting JAK/STAT signaling pathway in lung adenocarcinoma. Molecular carcinogenesis 49 32133692
2019 SIRT3 regulates cancer cell proliferation through deacetylation of PYCR1 in proline metabolism. Neoplasia (New York, N.Y.) 49 31108370
2019 PYCR1 interference inhibits cell growth and survival via c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathway in hepatocellular cancer. Journal of translational medicine 49 31619254
2020 RAC3 Promotes Proliferation, Migration and Invasion via PYCR1/JAK/STAT Signaling in Bladder Cancer. Frontiers in molecular biosciences 47 33062641
2013 DJ-1 cooperates with PYCR1 in cell protection against oxidative stress. Biochemical and biophysical research communications 45 23743200
2021 P5C as an Interface of Proline Interconvertible Amino Acids and Its Role in Regulation of Cell Survival and Apoptosis. International journal of molecular sciences 38 34769188
2008 Tailoring the structure of aminobisphosphonates to target plant P5C reductase. Journal of agricultural and food chemistry 36 18399639
2021 PYCR1 promotes bladder cancer by affecting the Akt/Wnt/β-catenin signaling. Journal of bioenergetics and biomembranes 31 33689096
2020 In crystallo screening for proline analog inhibitors of the proline cycle enzyme PYCR1. The Journal of biological chemistry 30 33109600
2019 A fragment-like approach to PYCR1 inhibition. Bioorganic & medicinal chemistry letters 30 31362921
2014 Human pyrroline-5-carboxylate reductase (PYCR1) acts on Δ(1)-piperideine-6-carboxylate generating L-pipecolic acid. Journal of inherited metabolic disease 29 24431009
2010 The phenotype caused by PYCR1 mutations corresponds to geroderma osteodysplasticum rather than autosomal recessive cutis laxa type 2. American journal of medical genetics. Part A 29 21204221
2023 Exosomes from PYCR1 knockdown bone marrow mesenchymal stem inhibits aerobic glycolysis and the growth of bladder cancer cells via regulation of the EGFR/PI3K/AKT pathway. International journal of oncology 28 37293856
2007 Plant P5C reductase as a new target for aminomethylenebisphosphonates. Journal of agricultural and food chemistry 26 17474756
2023 IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia. Nature communications 25 37777542
2019 The clinical significance of PYCR1 expression in renal cell carcinoma. Medicine 25 31305441
2011 Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome. American journal of medical genetics. Part A 24 22052856
2022 The role of PYCR1 in inhibiting 5-fluorouracil-induced ferroptosis and apoptosis through SLC25A10 in colorectal cancer. Human cell 23 36104652
2021 MiR-328-3p inhibits lung adenocarcinoma-genesis by downregulation PYCR1. Biochemical and biophysical research communications 23 33706104
2022 PYCR1 regulates glutamine metabolism to construct an immunosuppressive microenvironment for the progression of clear cell renal cell carcinoma. American journal of cancer research 21 36119844
2021 Deciphering the effects of PYCR1 on cell function and its associated mechanism in hepatocellular carcinoma. International journal of biological sciences 21 34239351
2018 Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations. Human genetics 21 30450527
2011 A novel mutation in PYCR1 causes an autosomal recessive cutis laxa with premature aging features in a family. American journal of medical genetics. Part A 21 21567914
2023 PYCR1 promotes the malignant progression of lung cancer through the JAK-STAT3 signaling pathway via PRODH-dependent glutamine synthesize. Translational oncology 20 37018868
2019 Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities. Cells 20 31091804
2019 PYCR1 is Associated with Papillary Renal Cell Carcinoma Progression. Open medicine (Warsaw, Poland) 19 31428683
2022 Survival and clinicopathological significance of PYCR1 expression in cancer: A meta-analysis. Frontiers in oncology 17 36119513
2021 Phenyl-substituted aminomethylene-bisphosphonates inhibit human P5C reductase and show antiproliferative activity against proline-hyperproducing tumour cells. Journal of enzyme inhibition and medicinal chemistry 14 34107832
2021 MiR-1207-5p targets PYCR1 to inhibit the progression of prostate cancer. Biochemical and biophysical research communications 13 34461437
2021 MicroRNA hsa-miR-150-5p inhibits nasopharyngeal carcinogenesis by suppressing PYCR1 (pyrroline-5-carboxylate reductase 1). Bioengineered 13 34696668
2022 SENP3 affects the expression of PYCR1 to promote bladder cancer proliferation and EMT transformation by deSUMOylation of STAT3. Aging 11 36227136
2021 Genetic analysis of Pycr1 and Pycr2 in mice. Genetics 11 33734376
2021 Isozymes of P5C reductase (PYCR) in human diseases: focus on cancer. Amino acids 11 34291342
2021 Knockdown of PYCR1 suppressed the malignant phenotype of human hepatocellular carcinoma cells via inhibiting the AKT pathway activation. Reproductive biology 10 34271243
2024 Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography. Journal of chemical information and modeling 9 38411104
2022 Epigenetic modification facilitates proline synthase PYCR1 aberrant expression in gastric cancer. Biochimica et biophysica acta. Gene regulatory mechanisms 9 35654390
2022 CRIF1 promotes the progression of non-small-cell lung cancer by SIRT3- mediated deacetylation of PYCR1. Journal of molecular histology 9 35716330
2022 miR-150-5p inhibits nasopharyngeal cancer genesis by suppressing PYCR1. The American journal of the medical sciences 9 35718122
2024 Screening a knowledge-based library of low molecular weight compounds against the proline biosynthetic enzyme 1-pyrroline-5-carboxylate 1 (PYCR1). Protein science : a publication of the Protein Society 8 39133178
2024 Crosstalk between FTH1 and PYCR1 dysregulates proline metabolism and mediates cell growth in KRAS-mutant pancreatic cancer cells. Experimental & molecular medicine 8 39294443
2023 LINC01123 acts as an oncogenic driver in lung adenocarcinoma by regulating the miR-4766-5p/PYCR1 axis. Histology and histopathology 8 36994814
2022 Low-dose radiation exaggerates HFD-induced metabolic dysfunction by gut microbiota through PA-PYCR1 axis. Communications biology 8 36088469
2025 Hypoxia-induced PYCR1 regulates glycolysis and histone lactylation to promote bladder cancer progression and metastasis via SLC6A14/Glutamine metabolism. Cancer biology & therapy 7 40808274
2024 Pro-tumorigenic activity of PYCR1 in gastric cancer through regulating the PI3K/AKT signaling. Heliyon 7 38455525
2025 Mechanism of SMYD2 promoting stemness maintenance of bladder cancer stem cells by regulating PYCR1 expression and PINK1/Parkin mitophagy pathway. International journal of oncology 5 40341538
2016 Clusterin and Pycr1 alterations associate with strain and model differences in susceptibility to experimental pancreatitis. Biochemical and biophysical research communications 5 27939882
2024 PYCR1 regulates TRAIL‑resistance in non‑small cell lung cancer cells by regulating the redistribution of death receptors. Oncology letters 4 38549801
2024 BHLHE41 inhibits bladder cancer progression via regulation of PYCR1 stability and thus inactivating PI3K/AKT signaling pathway. European journal of medical research 4 38811952
2024 PYCR1 expresses in cancer-associated fibroblasts and accelerates the progression of C6 glioblastoma. Histology and histopathology 4 38826151
2025 Effect and mechanism of PYCR1 on biological function of hepatocellular carcinoma cells under hypoxia. Discover oncology 3 40542176
2025 The key enzyme PYCR1 in proline metabolism: a dual driver of cancer progression and fibrotic remodeling. Journal of enzyme inhibition and medicinal chemistry 3 40891362
2025 Crystallographic fragment screening reveals new starting points for PYCR1 inhibitor design. Bioorganic chemistry 3 41016381
2024 A micropeptide TREMP encoded by lincR-PPP2R5C promotes Th2 cell differentiation by interacting with PYCR1 in allergic airway inflammation. Allergology international : official journal of the Japanese Society of Allergology 3 39025723
2022 Circ_0000705 facilitates proline metabolism of esophageal squamous cell carcinoma cells by targeting miR-621/PYCR1 axis. Discover oncology 3 35731336
2025 PYCR1 Promotes Esophageal Squamous Cell Carcinoma by Interacting With EGFR to Affecting the PI3K/Akt/mTOR Signaling Pathway. The journal of gene medicine 2 40102683
2025 The transcription factor FOXA1 upregulates PYCR1-mediated autophagy to suppress antitumor immunity in lung adenocarcinoma. Cancer immunology, immunotherapy : CII 2 40848149
2024 Please, carefully, pass the P5C. Journal of experimental botany 2 38307518
2024 ITPKA phosphorylates PYCR1 and promotes the progression of glioma. Heliyon 2 39170313
2022 Metabolomic and transcriptomic studies of improvements in myocardial infarction due to Pycr1 deletion. Journal of cellular and molecular medicine 2 36495058
2026 Integrating virtual screening and molecular dynamics simulations to identify emodin as a PYCR1 inhibitor modulating docetaxel sensitivity in prostate cancer. Journal of enzyme inhibition and medicinal chemistry 1 41665114
2025 The Proline Dehydrogenase Gene CsProDH1 Regulates Homeostasis of the Pro-P5C Cycle Under Drought Stress in Tea Plants. International journal of molecular sciences 1 40243904
2025 PYCR1 inhibition in bone marrow stromal cells enhances bortezomib sensitivity in multiple myeloma cells by altering their metabolism. Molecular oncology 1 40932053
2025 Glutamine metabolism reprogramming promotes bladder cancer progression via PYCR1: a multi-omics and functional validation study. Journal of translational medicine 1 41233804
2025 PYCR1 drives lung cancer progression through functional interactions with EGFR and TLR signaling pathways. Experimental & molecular medicine 1 41254241
2022 Functional Characterization of Saccharomyces cerevisiae P5C Reductase, the Enzyme at the Converging Point of Proline and Arginine Metabolism. Microorganisms 1 36296354
1991 Possible involvement of a L-delta 1-pyrroline-5-carboxylate (P5C) reductase in the synthesis of proline in Desulfovibrio desulfuricans Norway. Biochemical and biophysical research communications 1 1898390
2026 Multi-omics analyses related to mitochondria and ageing in triple-negative breast cancer implicate PYCR1 potentiates tumor progression. Cancer cell international 0 41749247
2026 PYCR1 Downregulation Induces Autophagy Dependent Apoptosis Through Inhibiting PI3K/AKT/mTOR Axis in Human Hepatocellular Carcinoma Cells. Analytical cellular pathology (Amsterdam) 0 41810929
2026 Study on the effects and mechanisms of M2 macrophages on PYCR1-promoted biological behavior of hepatocellular carcinoma cells. Scientific reports 0 41839921
2026 [Research Progress on the Role and Mechanisms of PYCR1 
in Tumorigenesis and Progression]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 0 41975648
2025 [A pan-cancer analysis of PYCR1 and its predictive value for chemotherapy and immunotherapy responses in bladder cancer]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 40294939
2025 9-Deazaadenosine directly binds PYCR1 and inhibits cancer cell proliferation through disruption of NAD+ metabolism. Translational oncology 0 40706441
2024 Confirming the enzymatic activity and neurodevelopmental trajectory of PYCR1 mutation in one child with autosomal-recessive cutis laxa type 2. Molecular genetics and genomics : MGG 0 39172257
2024 Successful Reduction of a Dislocated Hip Joint in a Patient With Cutis Laxa From a PYCR1 Mutation: Case Report. JBJS case connector 0 39739984

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